This application is a 371 of PCT/JP00/04279 filed Jun. 29, 2000.
The present invention relates to crystals of a benzimidazole compound that possesses an antiulcer action.
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof, which possess an antiulcer activity, has been described in JP 61-50978 A and the like.
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole possesses a chiral sulfur within the molecule, and two kinds of optical isomers thereof exist. As a result of intensive investigations, the present inventors have succeeded in the optical resolution and crystallization of the (S) isomer of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole and have found for the first time that the crystals are satisfactory enough for drugs, thereby having completed the present invention on the basis of these findings.
In other words, the present invention relates to
(1) crystals of (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof,
(2) crystals of (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,
(3) the crystals as described in the above (2) which possess a pattern of the powder X-ray diffraction whose characteristic peaks appear at the lattice spacing (d) of the powder X-ray diffraction of 11.68, 6.78, 5.85, 5.73, 4.43, 4.09, 3.94, 3.90, 3.69, 3.41, 3.11 angstrom (xc3x85),
(4) a pharmaceutical composition comprising the crystals as described in the above (1) and the like.
As for thexe2x80x9csaltxe2x80x9d of xe2x80x9c(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereofxe2x80x9d, a physiologically acceptable salt is preferred, which is exemplified by a metal salt, a salt with an organic base, a salt with a basic amino acid or the like.
Examples of a metal salt include an alkaline metal salt such as sodium salt, potassium salt, etc., an alkaline earth metal salt such as calcium salt, magnesium salt, barium salt, etc., and the like. A salt with an organic base is exemplified by a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine or the like. A salt with a basic amino acid is exemplified by a salt with arginine, lysine or the like.
Crystals of (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof may be a hydrate or a non-hydrate.
Said xe2x80x9chydratexe2x80x9d is exemplified by a 0.5 to 5.0 hydrate. Among them, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate, or 2.5 hydrate is preferable. Particularly preferred is 1.5 hydrate.
Crystals of (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof can be obtained by subjecting 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof to optical resolution or by subjecting 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole or a salt thereof to asymmetric oxidation to obtain the (S)-isomer, followed by crystallization.
Examples of a method used for the optical resolution include a per se known method such as a fractional recrystallization method, a chiral column method, a diastereomer method and the like. As asymmetric oxidation, a per se known method is used.
The xe2x80x9cfractional recrystallization methodxe2x80x9d is exemplified by a method, in which the racemate is treated with an optically active compound [e.g., (+)-mandelic acid, (xe2x88x92)-mandelic acid, (+)-tartaric acid, (xe2x88x92)-tartaric acid, (+)-1-phenethylamine, (xe2x88x92)-1-phenethylamine, cinchonine, (xe2x88x92)-cinchonidine, brucine, etc.) to form the salts, followed by separation by a fractional recrystallization or the like, and, optionally, by subjecting the resultant to a neutralization step to obtain the optical isomer in the free form.
The xe2x80x9cchiral column methodxe2x80x9d is exemplified by a method, in which the racemate or a salt thereof is applied to a column for separation of optical isomers (a chiral column). In the case of liquid chromatography, for instance, there is exemplified a method, in which the racemate is added to a chiral column such as ENANTIO-OVM (manufactured by Toso Corporation), CHIRAL series manufactured by Daicel Company or the like, which is eluted with water, a buffer solution (e.g., a phosphate buffer solution), an organic solvent (e.g., hexane, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, triethylamine, etc.) or a mixed solvent thereof to separate the optical isomers. In the case of gas chromatography, for instance, a separation method using a chiral column such as CP-Chirasil-DeX CB (manufactured by G-L Sciences Inc.) or the like is exemplified.
The xe2x80x9cdiastereomer methodxe2x80x9d is exemplified by a method, in which the racemate is allowed to react with an optically active reagent (preferably, to react with the optically active reagent at position 1 of the benzimidazole group) to obtain a mixture of the diastereomers, followed by treatment with a conventional separation means (e.g., fractional recrystallization, chromatography method, etc.) to obtain one of the diastereomers, which is then subjected to a chemical reaction (e.g., acid hydrolysis reaction, basic hydrolysis reaction, hydrogenolysis reaction, etc.) to cleave the moiety of the optically active reagent, thereby obtaining the objective optical isomer. Examples of said xe2x80x9coptically active reagentxe2x80x9d include optically active organic acids such as MTPA [xcex1-methoxy-xcex1-(trifluoromethyl)phenylacetic acid], (xe2x88x92)-menthoxyacetic acid and the like; optically active alkoxymethyl halides such as (1R-endo)-2-(chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1]heptane, and the like.
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof is produced according to the method described in JP 61-50978 A, U.S. Pat. No. 4,628,098 or the like, or a modified method thereof.
Examples of the method for crystallization include a per se known method such as crystallization from a solution, crystallization from a vapor, and crystallization from a melt.
Examples of the method for said xe2x80x9ccrystallization from a solutionxe2x80x9d include a concentration method, a slow cooling method, a reaction method (diffusion method or electrolysis method), a hydrothermal formation method, a fluxing agent method and the like. Examples of the solvent to be used include aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitrites (e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), acid amides (e.g., N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.), alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), water and the like. These solvents are used alone or in combination of two or more thereof in an adequate ratio (for example, 1:1 to 1:100).
Examples of the method for said xe2x80x9ccrystallization from a vaporxe2x80x9d include an evaporation method (a sealed tube method or an air stream method), a vapor phase reaction method, a chemical transportation method or the like.
Examples of the method for said xe2x80x9ccrystallization from a meltxe2x80x9d include a normal freezing method (pulling-up method, temperature gradient method or Bridgman method), a zone melting method (zone leveling method or float zone method), a special growth method (VLS method or liquid-phase epitaxy method) and the like.
As for an method for analyzing the thus-obtained crystals, generally, crystal analysis by a X-ray diffraction method is employed. Furthermore, a method for determining the orientation of crystals is exemplified by a mechanical method, an optical method or the like.
The thus-obtained crystals of (S)-2-[[[3-methyl-4-(2,2,3-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof (hereinafter, sometimes, abbreviated as xe2x80x9cthe crystals of the present inventionxe2x80x9d) possesses an excellent antiulcer activity, an anti-gastric acid secreting activity, a mucous membrane protecting activity, an anti-Helicobacter pylori activity and the like, and is useful as drugs owing to the low toxicity. Moreover, crystallization of the S-form not only increases the stability but also facilitates the handling of the compound, thereby making it possible to manufacture solid pharmaceutical compositions in a reproducible manner. Also, a shorter duration of the pharmacological activity is obtained in the case of administration of the crystals of the present invention, resulting in allowing a long-term administration.
The crystals of the present invention are useful for therapeutics and prophylaxis of a peptic ulcer (e.g., gastric ulcer, duodenal ulcer, stomal ulcer, Zollinger-Ellison""s syndrome, etc.), gastritis, reflux esophagitis, NUD (non-ulcer dyspepsia), stomach cancer, gastric MALT lymphoma and the like, eradication of Helicobacter pylori, suppression of bleeding of upper gastrointestinal tract caused by peptic ulcer, acute stress ulcer and hemorrhagic gastritis, suppression of bleeding of upper gastrointestinal tract caused by invasive stress (stress caused by major surgery requiring postoperative intensive care, cerebrovascular disorder requiring intensive treatment, head injury, multiple organ failure and extensive burn), therapeutics and prophylaxis of ulcer caused by a nonsteroidal antiinflammatory agent; therapeutics and prophylaxis of hyperacidity and ulcer caused by postoperative stress; pre-anesthetic medication, and the like, in mammals (e.g., human, monkey, sheep, cow, horse, dog, cat, rabbit, rat, mouse, etc.).
The crystals of the present invention are low in the toxicity and can be safely administered orally or parenterally (for example, local, rectal and intravenous administrations, or the like) as they are or as any of pharmaceutical compositions, which are prepared by mixing with pharmacologically acceptable carriers according to a per se known method, such as, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granular preparations, capsules (including soft capsules), oral disintegrating tablets, solutions, injectable preparations, suppositories, sustained release preparations, patches and the like.
The content of the crystals of the present invention in the pharmaceutical compositions of the present invention is about 0.01 to 100% by weight based on the total weight of the composition. Although the dose of any of said pharmaceutical compositions varies depending on particular patient, route of administration, disease and the like, in the case of oral administration to an adult (60 kg) as an antiulcer agent, for instance, the dose is about 0.5 to 1500 mg/day as the active ingredient, preferably about 5 to 150 mg/day. The daily dosage of the crystals of the present invention may be administered at once or divided into 2 to 3 times per day.
As for the pharmacologically acceptable carriers that may be used for the manufacture of the pharmaceutical compositions of the present invention, there are used a variety of conventional pharmaceutically acceptable organic or inorganic carrier substances, for example, excipients, lubricants, binding agents, disintegrators, water-soluble high molecular substances and basic inorganic salts for solid preparations; solvents, solubilizing agents, suspending agents, isotonicity agents, buffering agents and analgesics for liquid preparations, and the like. Also, as needed, additives such as conventional preservatives, antioxidants, coloring agents, sweeteners, acidifiers, foaming agents, flavors and the like can be used.
Examples of said xe2x80x9cexcipientsxe2x80x9d include lactose, white soft sugar, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, titanium oxide and the like.
Examples of said xe2x80x9clubricantsxe2x80x9d include magnesium stearate, a sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
Examples of said xe2x80x9cbinding agentsxe2x80x9d include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, xcex1-starch, polyvinyl pyrrolidone, gum arabic, gelatin, Pullulan, low-substituted hydroxypropyl cellulose and the like.
Examples of said xe2x80x9cdisintegratorsxe2x80x9d include (1) crospovidon, (2) a disintegrator that is designated as a super disintegrator such as croscarmellose sodium (FMC-Asahi Kasei), carmellose calcium (Gotoku Yakuhin) or the like, (3) carboxymethyl starch sodium (e.g., manufactured by Matsutani Kagaku Kabushiki Kaisha), (4) a low-substituted hydroxypropyl cellulose (e.g., manufactured by Shin-Etsu Kagaku Kabushiki Kaisha), (5) corn starch, and the like. Said xe2x80x9ccrospovidonxe2x80x9d may be any of crosslinked polymers that have a chemical name of 1-ethenyl-2-pyrrolidinone homopolymer, including polyvinyl polypyrrolidone (PVPP) and so-called 1-vinyl-2-pyrrolidinone homopolymer, where specific examples include Kollidon CL (manufactured by BASF AG), Polyplasdon XL (manufactured by ISP Company), Polyplasdon XL-10 (manufactured by ISP Company), Polyplasdon INF-10 (manufactured by ISP Company) and the like.
Examples of said xe2x80x9cwater-soluble high molecular substancesxe2x80x9d include an ethanol-soluble, water-soluble high molecular substance [for example, a cellulose derivative such as hydroxypropyl cellulose (hereinafter, may be described as HPC), polyvinyl pyrrolidone and the like], an ethanol-insoluble, water-soluble high molecular substance [for example, a cellulose derivative such as hydroxypropylmethyl cellulose (hereinafter, may be described as HPMC), methyl cellulose or carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like] and the like.
Examples of said xe2x80x9cbasic inorganic saltsxe2x80x9d include a basic inorganic salt of sodium, potassium, magnesium and/or calcium. Preferably, it is a basic inorganic salt of magnesium and/or calcium. More preferably, it is a basic inorganic salt of magnesium. Examples of said basic inorganic salt of sodium include sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate and the like. Examples of said basic inorganic salt of potassium include potassium carbonate, potassium hydrogen carbonate and the like. Examples of said basic inorganic salt of magnesium include magnesium carbonate heavy, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6Al2(OH)16xc2x7CO3xc2x74 H2O] and alumina magnesium hydroxide, preferably magnesium carbonate heavy, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like. Examples of said basic inorganic salt of calcium include precipitated calcium carbonate, calcium hydroxide and the like.
Examples of said xe2x80x9csolventsxe2x80x9d include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of said xe2x80x9csolubilizing agentsxe2x80x9d include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisamiomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of said xe2x80x9csuspending agentsxe2x80x9d include, a surface active agent such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate or the like; a hydrophilic, high molecular substance such as, for example, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or the like, and the like.
Examples of said xe2x80x9cisotonicity agentsxe2x80x9d include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of said xe2x80x9cbuffering agentsxe2x80x9d include a buffer solution of a phosphate, an acetate, a carbonate, a citrate or the like, and the like.
Examples of said xe2x80x9canalgesicsxe2x80x9d include benzyl alcohol and the like.
Examples of said xe2x80x9cpreservativesxe2x80x9d include a paraoxybenzoic acid ester, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of said xe2x80x9cantioxidantsxe2x80x9d include a sulfite salt, ascorbic acid, xcex1-tocopherol and the like.
Examples of said xe2x80x9ccoloring agentsxe2x80x9d include a food dye such as food yellow No. 5, food red No. 2, food blue No. 2 or the like; edible lake dye, iron oxide red and the like.
Examples of said xe2x80x9csweetenersxe2x80x9d include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, somatin and the like.
Examples of said xe2x80x9cacidifiersxe2x80x9d include citric acid (anhydrous citric acid), tartaric acid, malic acid and the like.
Examples of said xe2x80x9cfoaming agentsxe2x80x9d include sodium bicarbonate and the like.
Examples of said xe2x80x9cflavorsxe2x80x9d, which may be either synthetic or naturally occurring, include lemon, lime, orange, menthol, strawberry and the like.
The oral preparations can be manufactured according to a per se known method by adding to the crystals of the present invention, for examples, a bulking agent, a disintegrator, a binding agent, a lubricant and the like, and by subjecting the resulting mixture to compression molding, as needed, followed by coating according to a per se known method for the purpose of masking of the taste, enteric coating or durability. In the case of the manufacture of an enteric coated preparation, an intermediary phase may be provided between the enteric coated phase and the drug-containing phase, according to a per se known method, for the purpose of separating both phases.
In the case where the crystals of the present invention are used for the manufacture of an oral rapidly disintegrating tablet, there is exemplified a method comprising coating a core containing crystalline cellulose and lactose with the crystals of the present invention and a basic inorganic salt, followed by further coating with a coating layer containing a water-soluble high molecular substance to obtain a composition, coating the thus-obtained composition with an enteric coating layer containing polyethylene glycol, coating with an enteric coating layer containing triethyl citrate, coating with an enteric coating layer containing polyethylene glycol, further coating with mannitol to obtain fine granules, mixing the thus-obtained fine granules with an excipient and molding, or the like. Examples of the above-described xe2x80x9centeric coating layerxe2x80x9d include one or more of an aqueous-type enteric high molecular base such as cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, a methacrylate copolymer [e.g., Eudragit L30D-55 (trade name; manufactured by Rohm Company), Kollicoat MAE30DP (trade name; manufactured by BASF AG), Poliquid PA30 (trade name; manufactured by Sanyo Kasei Company), etc.], carboxymethylethyl cellulose, shellac or the like; a sustained-release base such as a methacrylate copolymer [e.g., Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.] or the like; a water-soluble high molecular substance; plasticizers such as triethyl citrate, polyethylene glycol, acetylated monoglyceride, triacetin, castor oil, etc., and the like. Examples of the above-described xe2x80x9cadditivesxe2x80x9d include a water-soluble sugar alcohol (e.g., sorbitol, mannitol, maltitol, reducing saccharized starch, xylitol, reducing palatinose, erythritol, etc.), crystalline cellulose (e.g., Ceolus KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose/carmellose sodium), etc.), a low substitution degree hydroxypropyl cellulose (e.g., LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Kagaku Kabushiki Kaisha), a mixture thereof, etc.) or the like, where there are further used a binding agent, an acidifier, a foaming agent, a sweetener, a flavor, a lubricant, a coloring agent, a stabilizer, an excipient, a disintegrator and the like.
The crystals of the present invention may be used together with 1 to 3 kinds of other active components.
Examples of said xe2x80x9cother active componentsxe2x80x9d include an anti-Helicobacter pylori substance, an imidazole compound, a bismuth salt, a quinolone compound and the like. Among these, an anti-Helicobacter pylori substance, an imidazole compound and the like are preferable. Examples of said xe2x80x9canti-Helicobacter pylori substancexe2x80x9d include a penicillin antibiotic (e.g., amoxicillin, benzyl penicillin, piperacillin, mecillinam, etc.), a cephem antibiotic (e.g., cefixime, cefaclor, etc.), a macrolide antibiotic (e.g., erythromycin, clarithromycin, etc.), a tetracycline antibiotic (e.g., tetracycline, minocycline, streptomycin, etc.), an aminoglycoside antibiotic (e.g., gentamycin, amikacin, etc.), imipenem and the like. A penicillin antibiotic, a macrolide antibiotic and the like are especially preferable. Examples of said xe2x80x9cimidazole compoundxe2x80x9d include metronidazole, miconazole and the like. Examples of said xe2x80x9cbismuth saltxe2x80x9d include bismuth acetate, bismuth citrate and the like. Examples of said xe2x80x9cquinolone compoundxe2x80x9d include ofloxacin, ciproxacin and the like.
Said xe2x80x9cother active componentsxe2x80x9d and the crystals of the present invention may be mixed and formulated into a single pharmaceutical composition (e.g., a tablet, a powder, a granule preparation, a capsule (including a soft capsule), a liquid and solution, an injection, a suppository, a sustained release preparation, etc.) according to a per se known method, or may be formulated separately and administered to the same subject at the same time or at a certain interval.